The genetics of type 2 diabetes and its clinical relevance

Clinical Genetics

Volumn 83, Issue 4, 2013, Pages 297-306

  Pal, A ^a   Mccarthy, M I ^a,b,c  

^a UNIVERSITY OF OXFORD   (United Kingdom)

^b UNIVERSITY OF OXFORD   (United Kingdom)

^c NIHR OXFORD BIOMEDICAL RESEARCH CENTRE   (United Kingdom)

Author keywords

Clinical; Diabetes; Diagnosis; Genetics; Genome wide association studies; Pathogenesis; Treatment; Variants

Indexed keywords

C REACTIVE PROTEIN; CYCLIN DEPENDENT KINASE INHIBITOR 2A; CYCLIN DEPENDENT KINASE INHIBITOR 2B; GLITAZONE DERIVATIVE; HEPATOCYTE NUCLEAR FACTOR 1BETA; INSULIN; INWARDLY RECTIFYING POTASSIUM CHANNEL SUBUNIT KIR6.2; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA COACTIVATOR 1ALPHA; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; SULFONYLUREA; SULFONYLUREA DERIVATIVE; THIAMINE; TRANSCRIPTION FACTOR 7 LIKE 2; BIOLOGICAL MARKER;

BODY MASS; CARDIOVASCULAR DISEASE; CLINICAL FEATURE; CLINICAL TRIAL (TOPIC); DIABETES MELLITUS; DIABETIC NEPHROPATHY; DIABETIC NEUROPATHY; DIABETIC RETINOPATHY; DISEASE ASSOCIATION; DISEASE CLASSIFICATION; DRUG MEGADOSE; ENVIRONMENTAL FACTOR; GENE EXPRESSION; GENE LOCUS; GENE MUTATION; GENE SEQUENCE; GENETIC ANALYSIS; GENETIC ASSOCIATION; GENETIC LINKAGE; GENETIC PREDISPOSITION; GENETIC SUSCEPTIBILITY; GENETIC TRAIT; GENETIC VARIABILITY; GENETICS; HEREDITY; HIGH THROUGHPUT SEQUENCING; HUMAN; INSULIN RELEASE; LOW DRUG DOSE; META ANALYSIS (TOPIC); MONOGENIC DIABETES; MONOGENIC DISORDER; NON INSULIN DEPENDENT DIABETES MELLITUS; PANCREAS ISLET BETA CELL; PATHOGENESIS; PEDIGREE ANALYSIS; PHARMACOGENETICS; PHENOTYPE; PREGNANCY DIABETES MELLITUS; PREVALENCE; PRIORITY JOURNAL; PROGNOSIS; REVIEW; RISK FACTOR; STRATIFIED SAMPLE;

BIOLOGICAL MARKERS; DIABETES MELLITUS, TYPE 2; GENETIC LOCI; GENETIC PREDISPOSITION TO DISEASE; HUMANS;

EID: 84874966710     PISSN: 00099163     EISSN: 13990004     Source Type: Journal    
DOI: 10.1111/cge.12055     Document Type: Review

References (100)

1. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004: 27 (5): 1047-1053.
2. Almgren P, Lehtovirta M, Isomaa B et al. Heritability and familiality of type 2 diabetes and related quantitative traits in the Botnia study. Diabetologia 2011: 54 (11): 2811-2819.
3. Owen K, Hattersley AT. Maturity-onset diabetes of the young: from clinical description to molecular genetic characterization. Best Pract Res Clin Endocrinol Metab 2001: 15 (3): 309-323.
4. O'Rahilly S, Farooqi IS. Genetics of Obesity. Philos Trans R Soc Lond B Biol Sci 2006: 361 (1471): 1095-1105.
5. Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science 1996: 273 (5281): 1516-1517.
6. Altshuler D, Hirschhorn JN, Klannemark M et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 2000: 26 (1): 76-80.
7. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem 1995: 270 (22): 12953-12956.
8. Gloyn AL, Weedon MN, Owen KR et al. Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes 2003: 52 (2): 568-572.
9. Grant SF, Thorleifsson G, Reynisdottir I et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 2006: 38 (3): 320-323.
10. Saxena R, Voight BF, Lyssenko V et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 2007: 316 (5829): 1331-1336.
11. Scott LJ, Mohlke KL, Bonnycastle LL et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 2007: 316 (5829): 1341-1345.
12. Sladek R, Rocheleau G, Rung J et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 2007: 445 (7130): 881-885.
13. Zeggini E, Weedon MN, Lindgren CM et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 2007: 316 (5829): 1336-1341.
14. Cho YS, Chen CH, Hu C et al. Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians. Nat Genet 2012: 44 (1): 67-72.
15. Dupuis J, Langenberg C, Prokopenko I et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 2010: 42 (2): 105-116.
16. Kooner JS, Saleheen D, Sim X et al. Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci. Nat Genet 2011: 43 (10): 984-989.
17. Palmer ND, McDonough CW, Hicks PJ et al. A genome-wide association search for type 2 diabetes genes in African Americans. PLoS One 2012: 7 (1): e29202.
18. Voight BF, Scott LJ, Steinhorsdottir V et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 2010: 42 (7): 579-589.
19. Morris AP, Voight BF, Teslovich TM et al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet 2012: 44 (9): 981-990.
20. Frayling TM. Genome-wide association studies provide new insights into type 2 diabetes aetiology. Nat Rev Genet 2007: 8 (9): 657-662.
21. Bonnefond A, Clément N, Fawcett K et al. Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes. Nat Genet 2012: 44 (3): 297-301.
22. Rung J, Cauchi S, Albrechtsen A et al. Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia. Nat Genet 2009: 41 (10): 1110-1115.
23. Frayling TM, Timpson NJ, Weedon MN et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007: 316 (5826): 889-894.
24. Freathy RM, Timpson NJ, Lawlor DA et al. Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI. Diabetes 2008: 57 (5): 1419-1426.
25. Lyssenko V, Nagorny CL, Erdos MR et al. Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nat Genet 2009: 41 (1): 82-88.
26. Prokopenko I, Langenberg C, Florez JC et al. Variants in MTNR1B influence fasting glucose levels. Nat Genet 2009: 41 (1): 77-81.
27. Unwin N, Shaw J, Zimmet P, Alberti KG. Impaired glucose tolerance and impaired fasting glycaemia: the current status on definition and intervention. Diabet Med 2002: 19 (9): 708-723.
28. Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 1992: 35 (7): 595-601.
29. Hattersley AT, Tooke JE. The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease. Lancet 1999: 353 (9166): 1789-1792.
30. Freathy RM, Bennett AJ, Ring SM et al. Type 2 diabetes risk alleles are associated with reduced size at birth. Diabetes 2009: 58 (6): 1428-1433.
31. Freathy RM, Mook-Kanamori DO, Sovio U et al. Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight. Nat Genet 2010: 42 (5): 430-435.
32. Freathy RM, Hayes MG, Urbanek M et al. Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study: common genetic variants in GCK and TCF7L2 are associated with fasting and postchallenge glucose levels in pregnancy and with the new consensus definition of gestational diabetes mellitus from the International Association of Diabetes and Pregnancy Study Groups. Diabetes 2010: 59 (10): 2682-2689.
33. Nicolson TJ, Bellomo EA, Wijesekara N et al. Insulin storage and glucose homeostasis in mice null for the granule zinc transporter ZnT8 and studies of the type 2 diabetes-associated variants. Diabetes 2009: 58 (9): 2070-2083.
34. Gaulton KJ, Nammo T, Pasquali L et al. A map of open chromatin in human pancreatic islets. Nat Genet 2010: 42 (3): 255-259.
35. Loder MK, da Silva Xavier G, McDonald A, Rutter G. TCF7L2 controls insulin gene expression and insulin secretion in mature pancreatic beta-cells. Biochem Soc Trans 2008: 36 (Pt 3): 357-359.
36. Rulifson IC, Karnik SK, Heiser PW et al. Wnt signaling regulates pancreatic beta cell proliferation. Proc Natl Acad Sci USA 2007: 104 (15): 6247-6252.
37. Smith U, Gale EA. Cancer and diabetes: are we ready for prime time? Diabetologia 2010: 53 (8): 1541-1544.
38. Holly JM, Perks CM. Cancer as an endocrine problem. Best Pract Res Clin Endocrinol Metab 2008: 22 (4): 539-550.
39. Gudmundsson J, Sulem P, Steinthorsdottir V et al. Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat Genet 2007: 39 (8): 977-983.
40. Thomas G, Jacobs KB, Yeager M et al. Multiple loci identified in a genome-wide association study of prostate cancer. Nat Genet 2008: 40 (3): 310-315.
41. Kim WY, Sharpless NE. The regulation of INK4/ARF in cancer and aging. Cell 2006: 127 (2): 265-275.
42. Krishnamurthy J, Ramsey MR, Ligon KL et al. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 2006: 443 (7110): 453-457.
43. Rane SG, Dubus P, Mettus RV et al. Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia. Nat Genet 1999: 22 (1): 44-52.
44. Holdt LM, Teupser D. Recent studies of the human chromosome 9p21 locus, which is associated with atherosclerosis in human populations. Arterioscler Thromb Vasc Biol 2012: 32 (2): 196-206.
45. Pasmant E, Laurendeau I, Heron D, Vidaud M, Vidaud D, Bieche I.. Characterization of a germ-line deletion, including the entire INK4/ARF locus, in a melanoma-neural system tumor family: identification of ANRIL, an antisense noncoding RNA whose expression coclusters with ARF. Cancer Res 2007: 67 (8): 3963-3969.
46. Visel A, Zhu Y, May D et al. Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice. Nature 2010: 464 (7287): 409-412.
47. Pal A, Barber TM, Van de Bunt M et al. PTEN mutations as a cause of constitutive insulin sensitivity and obesity. N Engl J Med 2012: 367 (11): 1002-1011.
48. Thanabalasingham G, Pal A, Selwood MP et al. Systematic assessment of etiology in adults with a clinical diagnosis of young-onset type 2 diabetes is a successful strategy for identifying maturity-onset diabetes of the young. Diabetes Care 2012: 35 (6): 1206-1212.
49. Reiner AP, Barber MJ, Guan Y et al. Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein. Am J Hum Genet 2008: 82 (5): 1193-1201.
50. Owen KR, Thanabalasingham G, James TJ et al. Assessment of high-sensitivity C-reactive protein levels as diagnostic discriminator of maturity-onset diabetes of the young due to HNF1A mutations. Diabetes Care 2010: 33 (9): 1919-1924.
51. Perry JR, Voght BF, Yengo L et al. Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases. PLoS Genet 2012: 8 (5): e1002741.
52. Timpson NJ, Lindgren CM, Weedon MN et al. Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data. Diabetes 2009: 58 (2): 505-510.
53. Knowler WC, Barrett-Connor E, Fowler SE et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002: 346 (6): 393-403.
54. Lindstrom J, Louheranta A, Mannelin M et al. The Finnish Diabetes Prevention Study (DPS): lifestyle intervention and 3-year results on diet and physical activity. Diabetes Care 2003: 26 (12): 3230-3236.
55. Pan XR, Li GW, Hu YH et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: the Da Qing IGT and Diabetes Study. Diabetes Care 1997: 20 (4): 537-544.
56. Tuomilehto J, Lindström J, Eriksson JG et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001: 344 (18): 1343-1350.
57. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 2002: 359 (9323): 2072-2077.
58. Gerstein HC, Yusuf S, Bosch J et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006: 368 (9541): 1096-1105.
59. Torgerson JS, Hauptman J, Boldrin MN, Sjostrom L.. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 2004: 27 (1): 155-161.
60. Florez JC, Jablonksi KA, Bayley N et al. TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med 2006: 355 (3): 241-250.
61. Wang J, Kuusisto J, Vänttinen M et al. Variants of transcription factor 7-like 2 (TCF7L2) gene predict conversion to type 2 diabetes in the Finnish Diabetes Prevention Study and are associated with impaired glucose regulation and impaired insulin secretion. Diabetologia 2007: 50 (6): 1192-1200.
62. Grant RW, Hivert M, Pandiscio JC, Florez JC, Nathan DM, Meigs JB. The clinical application of genetic testing in type 2 diabetes: a patient and physician survey. Diabetologia 2009: 52 (11): 2299-2305.
63. Meigs JB, Shrader P, Sullivan LM et al. Genotype score in addition to common risk factors for prediction of type 2 diabetes. N Engl J Med 2008: 359 (21): 2208-2219.
64. Lyssenko V, Jonsson A, Almgren P et al. Clinical risk factors, DNA variants, and the development of type 2 diabetes. N Engl J Med 2008: 359 (21): 2220-2232.
65. Lango H, UK Type 2 Diabetes Genetics Consortium, Palmer CN et al. Assessing the combined impact of 18 common genetic variants of modest effect sizes on type 2 diabetes risk. Diabetes 2008: 57 (11): 3129-3135.
66. Talmud PJ, Hingorani AD, Cooper JA et al. Utility of genetic and non-genetic risk factors in prediction of type 2 diabetes: Whitehall II prospective cohort study. BMJ 2010: 340: b4838.
67. de Miguel-Yanes JM, Shrader P, Pencina MJ et al. Genetic risk reclassification for type 2 diabetes by age below or above 50 years using 40 type 2 diabetes risk single nucleotide polymorphisms. Diabetes Care 2011: 34 (1): 121-125.
68. Stahl EA, Wegmann D, Trynka G et al. Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis. Nat Genet 2012: 44 (5): 483-489.
69. Baptista PV. Principles in genetic risk assessment. Evidence for genetic susceptibility to diabetic nephropathy. Ther Clin Risk Manag 2005: 1 (1): 15-20.
70. Seaquist ER, Goetz FC, Rich S, Barbosa J.. Familial clustering of diabetic kidney disease. N Engl J Med 1989: 320 (18): 1161-1165.
71. Earle K, Walker J, Hill C, Vilberti G. Familial clustering of cardiovascular disease in patients with insulin-dependent diabetes and nephropathy. N Engl J Med 1992: 326 (10): 673-677.
72. Pezzolesi MG, Skupien J, Mychaleckyj JC, Warram JH, Krolewski AS.. Insights to the genetics of diabetic nephropathy through a genome-wide association study of the GoKinD collection. Semin Nephrol 2010: 30 (2): 126-140.
73. Pezzolesi MG, Poznik GD, Mychaleckyj JC et al. Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1 diabetes. Diabetes 2009: 58 (6): 1403-1410.
74. Pezzolesi MG, Poznik GD, Skupien J et al. An intergenic region on chromosome 13q33.3 is associated with the susceptibility to kidney disease in type 1 and 2 diabetes. Kidney Int 2011: 80 (1): 105-111.
75. Mooyaart AL, Valk EJ, van Es LA et al. Genetic associations in diabetic nephropathy: a meta-analysis. Diabetologia 2011: 54 (3): 544-553.
76. Benetti E, Caridi G, Vella MD et al. Immature renal structures associated with a novel UMOD sequence variant. Am J Kidney Dis 2009: 53 (2): 327-331.
77. Serafini-Cessi F, Malagolini N, Cavallone D. Tamm-Horsfall glycoprotein: biology and clinical relevance. Am J Kidney Dis 2003: 42 (4): 658-676.
78. Gudbjartsson DF, Holm H, Indridason OS et al. Association of variants at UMOD with chronic kidney disease and kidney stones-role of age and comorbid diseases. PLoS Genet 2010: 6 (7): e1001039.
79. Kottgen A, Glazer NL, Dehghan A et al. Multiple loci associated with indices of renal function and chronic kidney disease. Nat Genet 2009: 41 (6): 712-717.
80. Padmanabhan S, Melander O, Johnson T et al. Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension. PLoS Genet 2010: 6 (10): e1001177.
81. Ahluwalia TS, Lindholm E, Groop L, Melander O. Uromodulin gene variant is associated with type 2 diabetic nephropathy. J Hypertens 2011: 29 (9): 1731-1734.
82. Pearson ER, Starkey BJ, Powell RJ, Gribble FM, Clark PM, Hattersley AT.. Genetic cause of hyperglycaemia and response to treatment in diabetes. Lancet 2003: 362 (9392): 1275-1281.
83. Pearson ER, Flechtner I, Njølstad PR et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med 2006: 355 (5): 467-477.
84. Becker ML, Visser LE, van Schaik RH, Hofman A, Uitterlinden AG, Stricker BH. Genetic variation in the multidrug and toxin extrusion 1 transporter protein influences the glucose-lowering effect of metformin in patients with diabetes: a preliminary study. Diabetes 2009: 58 (3): 745-749.
85. Jablonski KA, McAteer JB, de Bakker PI et al. Common variants in 40 genes assessed for diabetes incidence and response to metformin and lifestyle intervention in the diabetes prevention program. Diabetes 2010: 59 (10): 2672-2681.
86. Shu Y, Sheardown SA, Brown C et al. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest 2007: 117 (5): 1422-1431.
87. Zhou K, Bellenquez C, Spencer CC et al. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet 2011: 43 (2): 117-120.
88. Foretz M, Hébrad S, Leclerc J et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest 2010: 120 (7): 2355-2369.
89. Woods A, Leiper JM, Carling D. The role of ATM in response to metformin treatment and activation of AMPK. Nat Genet 2012: 44 (4): 360-361.
90. Pearson ER, Donnelly LA, Kimber C et al. Variation in TCF7L2 influences therapeutic response to sulfonylureas: a GoDARTs study. Diabetes 2007: 56 (8): 2178-2182.
91. Feng Y, Mao G, Ren X et al. Ser1369Ala variant in sulfonylurea receptor gene ABCC8 is associated with antidiabetic efficacy of gliclazide in Chinese type 2 diabetic patients. Diabetes Care 2008: 31 (10): 1939-1944.
92. Sesti G, Laratta E, Cardellini M et al. The E23K variant of KCNJ11 encoding the pancreatic beta-cell adenosine 5′-triphosphate-sensitive potassium channel subunit Kir6.2 is associated with an increased risk of secondary failure to sulfonylurea in patients with type 2 diabetes. J Clin Endocrinol Metab 2006: 91 (6): 2334-2339.
93. Hamming KS, Soliman D, Matemisz LC et al. Coexpression of the type 2 diabetes susceptibility gene variants KCNJ11 E23K and ABCC8 S1369A alter the ATP and sulfonylurea sensitivities of the ATP-sensitive K(+) channel. Diabetes 2009: 58 (10): 2419-2424.
94. Bluher M, Lubben G, Paschke R. Analysis of the relationship between the Pro12Ala variant in the PPAR-gamma2 gene and the response rate to therapy with pioglitazone in patients with type 2 diabetes. Diabetes Care 2003: 26 (3): 825-831.
95. Kang ES, Park SY, KIm HJ et al. Effects of Pro12Ala polymorphism of peroxisome proliferator-activated receptor gamma2 gene on rosiglitazone response in type 2 diabetes. Clin Pharmacol Ther 2005: 78 (2): 202-208.
96. Snitker S, Watanabe RM, Ani I et al. Changes in insulin sensitivity in response to troglitazone do not differ between subjects with and without the common, functional Pro12Ala peroxisome proliferator-activated receptor-gamma2 gene variant: results from the Troglitazone in Prevention of Diabetes (TRIPOD) study. Diabetes Care 2004: 27 (6): 1365-1368.
97. Wolford JK, Yeatts KA, Dhanjal SK et al. Sequence variation in PPARG may underlie differential response to troglitazone. Diabetes 2005: 54 (11): 3319-3325.
98. Lupski JR, Belmont JW, Boerwinkle E, Gibbs RA.. Clan genomics and the complex architecture of human disease. Cell 2011: 147 (1): 32-43.
99. Keinan A, Clark AG. Recent explosive human population growth has resulted in an excess of rare genetic variants. Science 2012: 336 (6082): 740-743.
100. Zuk O, Hechter E, Sunyaev SR, Lander ES. The mystery of missing heritability: genetic interactions create phantom heritability. Proc Natl Acad Sci USA 2012: 109 (4): 1193-1198.